Project Summary/Abstract Prenatal alcohol exposure can lead to devastating effects on the developing cerebral cortex, thereby causing a wide spectrum of neurological and psychiatric conditions after birth. One of the promising intervention approaches lies in enhancing intrinsic protective mechanisms to overwhelm the triggered pathological mechanisms. Therefore, understanding the defense mechanisms deployed by neural cells is imperative for the development of potential therapies for alcohol-induced neuropsychiatric conditions. The goal of the proposed study is to characterize a new pathway by which primary cilia could suppress the adverse impact of alcohol on developing cortical neurons. The primary cilium is a unique organelle which is known to be essential for a cell to sense and respond to environmental changes. However, the role of cilia during brain development, particularly, in harsh prenatal environment such as exposure to alcohol or other environmental stressors remains largely unknown. By combining a mouse model of cilia deficiency specifically in the cerebral cortex and alcohol exposure during the brain sprout stage, we found evidences that support our hypothesis; cilia may play a critical role in protecting cortical neurons from alcohol-inducible dendritic/spine degeneration or/and other permanent morphological alterations. We will test this hypothesis by characterizing cortical phenotypes of cilia-deficient conditional knockout mice exposed to alcohol (Aim1), and testing candidate molecular mechanisms which may mediate cilia-dependent inhibition of dendritic/spine degeneration in vivo (Aim2).